Our previous studies in awake sheep have shown that the cerebral blood flow (CBF) vasoconstriction response to hypocapnia is attenuated following exposure to 96 h of hypoxia (arterial PO2 = 40 torr). Human studies at altitude support this observation. In addition we have found that the cerebral vasodilator response to moderate hypoxia is depressed also following ventilatory acclimatization (VA). We propose in this study to expose conscious sheep to varying levels of inspired CO2 during hypoxia and hyperoxia before and following VA in order to determine whether there is a functional resetting of the point about which CBF is regulated in relation to CO2 and whether there is a change in the CBF sensitivity (slope) to CO2. Total and regional CBF will be measured using 15 micron radiolabelled microspheres. We also plan to carry out similar studies while varying inspired 02 levels before and after VA while measuring cerebral metabolic rate of 02 (CMRO/2) and the cerebral fractional extraction of 02. In this way we will also determine whether there is a long term functional resetting or change in sensitivity to the CBF response to 02. In additional studies, adenosine will be infused into the brain to see if the altered CBF response to 02 is paralleled by an altered CBF response to adenosine. Also, unilateral cerebral sympathectomy will be performed to determine whether these altered CBF responses are caused by altered sympathetic activity. Intracranial pressure will be measured to monitor the development of high altitude cerebral edema. This study will provide clearer insights into mechanisms which regulate CBF and breathing in chronic hypoxia and in disease states which manifest disorders of CBF. It may ultimately provide a model for the study of high-altitude brain edema.